upgrading pharmaceutical test methods using a contract...

30 Pharmaceutical Technology OUTSOURCING RESOURCES 2002 www.pharmtech.com

n the highly regulated pharmaceuti-cal industry, methods validation docu-mentation must support the suit-ability of analytical test methods for

drug substances and drug products. Asuitable method consistently provides ac-curate results under a normal range ofoperating conditions, with the goal ofevaluating samples to determine whetherthey meet the product’s specifications.Validated test methods ensure that prod-ucts are safe and effective and have ap-propriate storage conditions and expiryperiods.

Methods validation guidelines are be-coming more standardized across regula-

Upgrading Pharmaceutical Test MethodsUsing a Contract ResearchOrganization Paul Newton

Paul Newton, PhD, is atechnical project manager in thequality assurance department atGlaxoSmithKline, 1011 N.Arendell Ave., Zebulon, NC27597, tel. 919.269.1730,[email protected].

Methods validation guidelinesare becoming more standardizedacross regulatory jurisdictions.With the adoption of theInternational Conference onHarmonization’s (ICH)guidelines, test methods formature drugs must be validatedto current regulatory standards.This article discusses how asponsor company can select andpartner with a CRO to evaluate,redevelop, and revalidate theanalytical test methods used forits mature drug substances anddrug products.

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tory jurisdictions, especially since theadoption of the International Conferenceon Harmonization’s (ICH) guidelines. Al-though these guidelines are typically in-voked for new pharmaceuticals, test meth-ods for mature drugs should also bevalidated to current regulatory standards.If methods are not updated, FDA can issue483s to companies that either do not useappropriate methods or lack satisfactoryvalidation documentation. In Europe,companies must reregister drug productsevery five years to ensure that analyticalmethods for mature drugs meet currentstandards.

This article discusses how a pharma-

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ceutical (sponsor) company can select and partnerwith a CRO to evaluate, redevelop, and revalidatethe analytical test methods used for its mature mar-keted drug substances and drug products. To beginthe process, the sponsor should provide the CROwith background information regarding its exist-ing products and test methods. The CRO’s re-sponsibilities can include evaluating the suitabil-ity of any questionable test methods that mayrequire enhancement or replacement, enhancingexisting methods, developing new methods, vali-dating methods, and transferring new methods tothe appointed sponsor sites and writing the corre-sponding documents.

Project scope and outlineTests that may be evaluated include assay, relatedimpurities, dissolution, organic volatile impurities,content uniformity, controlled product excipients,and preservatives contained in the final dosageform. Methods validation standards and validationprotocols should be based on the most current ICHguidelines to meet global regulatory, pharma-copeial, and company standards. The followingsteps are examples of those that a methods valida-tion project may include:� Existing test methods and methods validation

documentation are assessed for suitability. Thisprocedure involves reviewing regulatory filingsand communications to determine whether thebasic chemistry of active ingredients was under-stood. Assay methods must be specific; those thatmeasure degradation product or impurity profiles must quan-tify impurities to sufficiently low levels. Existing methods vali-dation documentation must be reviewed to determine whetherit meets current standards. Feedback from laboratory ana-lysts with experience using these methods is also required.This part of the project may be performed by the sponsorcompany.

� Questionable methods are evaluated for their suitability fortheir intended uses as well as for their conformity with cur-rent standards.

� Unsuitable methods require redevelopment and full valida-tion.

� Suitable methods are required to be fully validated to currentstandards.

� If previously unobserved impurities are discovered at signifi-cant (i.e., at or above ICH threshold) levels, they are identi-fied, and it is ensured that they are quantified in the new testmethod.

� Regulatory and pharmacopeial submissions and laboratorydeployment also require attention but are not addressed inthis article.

Choosing internal or external resources to perform laboratory workA sponsor company should answer the following questions

when deciding whether to use in-house and/or contract re-sources to complete a project:� Does the sponsor possess sufficient available expertise, su-

pervision, laboratory and support staff, equipment, and spaceto do the job in house within the required time frame?

� Will in-house staff feel overburdened by this project, or willthey view it as a new challenge and an opportunity for pro-fessional development?

� Will this project be a distraction from the in-house staff ’s coreactivities?

� Will urgent core activities claim the project team’s laboratorystaff, supervision, and equipment and therefore underminethis noncore methods enhancement project?Complex projects of this type present scientific challenges as

well as heavy demands on time and human resources. Contractlaboratories may have considerably more experience in devel-oping and validating analytical methods than do some spon-sor groups, given the noncore nature of such activities.

Deciding the working arrangementsOnce a pharmaceutical company decides to outsource at leastpart of a methods validation project, it must decide how bestto use the CRO’s resources. This task can be accomplished bytaking one of at least three different approaches, including project-by-project, combined staff, or segregated staff.

Test Methods


Project-by-project approach. Projects are defined and assignedto the CRO on a project-by-project basis. For relatively smalljobs, project-by-project pricing and planning can work best be-cause establishing a fair value for the required work can usu-ally be accurately estimated. Because every project is unique,accurately estimating the costs on the basis of time involvedmay be more difficult as the tasks become more nonroutine.One advantage of this approach is that the sponsor does nothave to worry about keeping the contractor continuously busyto receive full value. A potential disadvantage of this approachis that many CRO staff members may work on a large projectand not become familiar with the sponsor’s corporate cultureor other special requirements.

Combined-staff approach. Full-time CRO staff are assigned tothe sponsor’s site. CRO staff hours are usually billed at an agreed-upon rate for a specific period of time, a plan that works verywell for large projects. This approach eliminates the need to es-timate resources that may be required for subprojects. If theCRO’s staff works at the sponsor’s facility, it may be managed

as the sponsor feels appropriate either by in-house or CRO supervisors. Communicationbetween the sponsor’s and contractor’s staffsis facilitated through close physical proximity.Moreover, any equipment and systems broughtin may be closely monitored for compatibilitywith the sponsor’s. The sponsor’s managementteam may also observe how effectively theCRO’s staff is working. One reason to avoidthis approach is that space, equipment, sup-port, and possibly supervision may have to bemade available for the CRO’s staff.

Segregated-staff approach. Full-time CRO staffwork at the contractor’s site. This approachavoids tying up the sponsor’s resources, al-though the physical separation of CRO andsponsor teams can make communication moredifficult. Sufficient time must be spent build-ing relationships and trust between the CROand the sponsor during the initial phases of theproject. The sponsor must supply sufficient in-formation, materials, and documentation in atimely fashion to make the best use of theCRO’s time and effort.

Considerations when choosing a CROMany CROs provide analytical chemistry ser-vices. Because certain CROs are better suitedto certain types of projects or sponsor compa-nies, a sponsor should exercise care whenchoosing a CRO for a specific project becausechoosing the wrong CRO can be very costly. Asponsor should consider a CRO’s reputation,CGMP compliance, experience, available re-sources, location, prices, and professional com-patibility before making this decision.

Reputation. The CRO’s reputation for in-tegrity, especially if problems arise, is an ab-

solute requirement. References from inside or outside the spon-sor’s organization or those obtained from professionalorganizations are indispensable. The CRO should provide ref-erences from similar projects that were completed with othersponsors.

CGMP–CGLP compliance. All standard operating procedures(SOPs) must be documented and conform to CGMP–CGLPguidelines. The CRO’s SOPs and other relevant work proce-dures should be reviewed along with any recent regulatory in-spection reports. An audit of its facility and a meeting with theappropriate CRO staff should also be scheduled.

Experience. Although many good CROs routinely performproduct release or stability testing, they are not necessarily quali-fied to perform methods evaluation, development, or valida-tion. These activities require a thorough understanding of ana-lytical chemistry and the ability to design meaningfulexperiments that help detect and solve nonroutine problems.Methods development and validation for highly regulated pharmaceuticals can be completely different from developing


test methods for other chemical samples. Experience with spe-cific classes of compounds or dosage forms may be especiallyvaluable.

Available laboratory, equipment, and staffing resources. An overlycrowded laboratory should be avoided. Equipment required forthe project should be properly qualified, calibrated, maintained,and documented. An experienced, high-quality CRO with first-line supervision and laboratory staff is essential. Contact withthe CRO staff is important when evaluating the communica-tion between the sponsor company and the CRO.

Location. The CRO’s location may be a factor in conductinga project efficiently. Proximity to the sponsor company or anairport can be an advantage for meetings and for deliveringsamples or special supplies. Video conferences or other com-munication aids the CRO plans to use must be compatible withthe sponsor company’s equipment.

Price. The CRO’s need for a reasonable profit and the spon-sor’s need for high value are not necessarily mutually exclusive.The lowest price to complete a project or the lowest hourly ratemay not always be the best value. The quality of the work andfinal deliverables, amount of direction and rework required,timeliness of project completion, compliance to CGLPs, and soforth all must be considered when measuring the value of theservices received.

Professional compatibility or chemistry. This characteristic canbe difficult to evaluate initially but will become very obviousand important after the project has begun. If the sponsor’s staffdoes not work well with the staff the CRO has assigned to a proj-ect, it will probably have an unpleasant experience, and the proj-ect may not be as successful as it could be. This attribute is dif-ficult to define but is a very real and powerful influence on thedaily execution and overall success of a project. Developing pro-fessional chemistry requires one or more managers at the spon-sor’s company to interact with their CRO counterparts early inthe project, preferably before it begins.

The contractRegardless of what was discussed and agreed to during the eval-uation period, the contract must contain all essential work speci-fications written in a timeline that includes major milestonesand a cost breakdown. The sponsor’s legal department shouldbe involved from the earliest stage of contract negotiations. Es-timating required resources for a nonroutine project is difficultbecause it is hard to predict how much work will be required

for each step of the project. Sometimes everything falls intoplace; at other times, every potential problem that can arise will.Building flexibility into the contract is important in case some-thing unforeseen occurs. The sponsor and the CRO should agreeabout confidentiality; ownership; billing and payment issues;a clear description of all deliverables; the sponsor’s responsi-bilities versus the CRO’s responsibilities; communication agree-ments; equipment and material costs; analysts’ sick time, vaca-tion, holidays, overtime, and training; how the project will bemanaged; how progress will be tracked and communicated;shipping costs; and surplus samples. A general master agree-ment between the CRO and sponsor may be advantageous.Then, specific project work orders can be submitted contain-ing the details of each project that is included in the generalmaster agreement.

The teamOnce the contract is signed, a team of analysts will be assignedto the project. These individuals must possess the skills ap-propriate for their tasks. Overskilled individuals may lose in-terest and end up costing more than necessary. Underskilledstaff may become overwhelmed, make poor decisions, workinefficiently, and even arrive at incorrect conclusions. Often ateam is no stronger than the supervisor. Having the right CROsupervisor can make the difference between the success andfailure of the overall project. The supervisor must not only un-derstand the project goals and details, possess the appropriateskills, and communicate well with and motivate the CRO staff,but he or she must also be adept at communicating with thesponsor company.

The overall planAn overall plan is indispensable to complete the work properlyand on schedule. Even the most-skilled team members will notmeet the project requirements unless they know precisely whois responsible for what. Uncommunicated assumptions are theenemy and downfall of good intentions and unwritten plans.Some issues to communicate in detail are� the final deliverables, including the required format, software,

signatures, and so forth. Model documents should be sharedto help clarify exactly what is needed.

� materials and information that are required from the spon-sor. The plan should clearly document how much of what isneeded, when it is needed, and any special requirements re-lated to delivering the product and keeping the project run-ning smoothly.

� specific responsibilities of the CRO and the sponsor company,including responsibility for decision making, problem solv-ing, and reviewing draft and final documents.

� milestones, timelines, and deadlines. These should be clearlystated in detail.

� finished product. This may not be obvious to the CRO. It mayinclude all the laboratory work, the draft documents, the is-sued documents, or the documents once approved by thesponsor laboratory. The contract should specify how addi-tional work beyond the original scope will be defined, ac-complished, and paid for.

Test Methods

An overall plan is indispensable

to complete the work properly

and on schedule—every team

member should know precisely

who is responsible for what.


� expected quality. This should be defined as clearly as possi-ble, as should be the degree of complexity for the finishedproduct and who will measure and determine whether theseexpectations have been met. Lack of sufficient detail may causethe work performed to be of little or no value. Model docu-ments can help the CRO understand what is required in eachsection of the document.

� changes that may be necessary after work has begun or evenafter completion. Making changes because of lack of fore-thought or communication can be extremely frustrating andwasteful. Time spent up front understanding and communi-cating what is required of the CRO is usually time well spent.Even the best plans may have to be revised in today’s quicklychanging work environment. Agreed-upon cost and timelinechanges caused by modifications to the scope of work, process,requirements, and plan should be documented.

The communication planA communication plan can add significant value to the projectand prevent unwanted surprises. Adequate up-front commu-nication is absolutely vital to the success of the project. Rush-ing into a project before communication lines have been established can be a recipe for ineffectiveness, frustration, stress,and failure. It is important to make no assumptions and to com-municate and thoroughly document agreements. Periodic meet-ings at regularly scheduled times can help ensure adequate com-

munication. Each meeting should have an agenda and allowtime for open discussion. The CRO and sponsor also shouldagree about the protocol for less-formal communications. Back-up personnel should be assigned to cover the times that theprincipals are not in the office. Before any emergencies arise,the principals may want to make known how they can be con-tacted outside of work and what kind of an emergency wouldrequire such communication.

Monitoring progressThis responsibility can be surprisingly difficult for a complexproject and can consume a huge amount of both CRO and spon-sor time. Too much time spent on planning and monitoring canbe self defeating because it consumes resources that could bebetter applied to completing the project. Overly detailed docu-mentation and the need to justify why everything is not exactlyon schedule can be counterproductive. On the other hand, it isimportant to monitor progress according to the timeline andbudget to ensure that the schedule is met and that costs are notout of line. The goal is to strike a balance between monitoringand working toward completion of the project.

The CRO and sponsor should discuss and agree up frontabout exactly what should drive the progress of the project if itstarts to fall behind schedule. In other words, which factors havepriority? Sometimes, as a result of unforeseen problems or in-accurate estimations of the resources required to perform a task,

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one objective must have priority over another. This distinctionshould be made as early as possible in the project.

Creating a win–win environmentBoth the CRO and sponsor can benefit from their working re-lationship. This requires working together as partners to a mu-tual advantage and toward defined goals. Unlike a sporting event,one side doesn’t have to lose for the other to win. The sponsorshould support the CRO in accomplishing its objectives as ef-fectively as possible. The CRO should be vigilant in helping thesponsor company obtain the best value for its money. If bothgroups consistently support and help each other meet theircommitments, they will create a win–win situation. It is im-portant not to do or say things that will destroy the trust andpositive relationship between the two organizations, while atthe same time remaining honest and straightforward in all deal-ings and communications. Constructive criticism can be valu-able if presented appropriately and in the spirit of being help-ful rather than just finding fault or assigning blame. The workexperience will be more positive for everyone, and both com-panies will profit if a true team spirit is developed across com-pany boundaries.

Lessons and experiencePeriodically, especially after project completion, project man-agers should schedule time to review the lessons learned from

project experiences. Both the CRO and sponsor should exploreand document what worked well and what might be improvedin the next project. These lessons may be applied to intracom-pany and intercompany teams. For both companies to preparebetter resource estimates for future projects, they should trackall work hours spent on the project and organize them into pre-defined categories.

ConclusionThe broad analytical knowledge and resources available at aCRO are valuable to achieve analytical solutions quickly. An ex-cellent team spirit can be developed as the project progressesand can increase the effectiveness and enjoyment of the pro-ject. Both the CRO and the sponsor company can gain experi-ence and knowledge from each other, and both companies willbe better prepared to take on similar projects in the future.

On the basis of a positive first experience with a CRO for thistype of project, a sponsor company can plan to significantly in-crease the involvement of the same CRO in similar future pro-jects. This can ensure that a nonroutine project will be con-ducted efficiently and its goals will be met with minimaldisruption to a sponsor company’s usual core activities. PT

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upgrading pharmaceutical test methods using a contract...

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